Monocyte polarization in children with falciparum malaria: relationship to nitric oxide insufficiency and disease severity

Abstract

We earlier established that nitric oxide (NO) is protective against severe malaria and that arginine and NO levels are reduced in malaria patients. We now show that an M2-like blood monocyte phenotype is significantly associated with hypoargininemia, NO insufficiency, and disease severity in Tanzanian children with falciparum malaria. Compared to control children (n = 106), children with moderately severe (n = 77) and severe falciparum malaria (n = 129) had significantly higher mononuclear cell arginase 1 mRNA, protein, and enzyme activity; lower NOS2 mRNA; lower plasma arginine; and higher plasma IL-10, IL-13, and IL-4. In addition, monocyte CD206 and CD163 and plasma soluble CD163 were elevated. Multivariate logistic regression analysis revealed a significant correlation of risk of severe malaria with both plasma IL-10 and soluble CD163 levels. Monocyte M2 skewing likely contributes to NO bioinsufficiency in falciparum malaria in children. Treatments that reverse the M2 polarization may have potential as adjunctive treatment for malaria.

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

“…Instead, decreased arginine and citrulline appearance seem to be primarily responsible for plasma arginine depletion. Our results do not directly contradict prior observations of increased host-and parasitederived arginase activity [2,7,10]; increased arginase activity may be required to preserve the rate of conversion of plasma arginine to ornithine in the setting of low arginine levels. However, our mouse model results demonstrate that any increase in arginase activity is secondary to the major effect of decreased arginine and citrulline appearance.…”

“…Host arginase could also contribute to arginine depletion via intracellular activation by cell-free heme [8] or via direct release into plasma during parasite-mediated hemolysis. Consistent with this hypothesis, increased plasma arginase activity has been associated with severe malaria in studies of Indonesian adults [2], Malian children [9], and Tanzanian children [10]. The latter study also demonstrated elevated peripheral blood mononuclear cell arginase 1 messenger RNA expression [10].…”

“…Consistent with this hypothesis, increased plasma arginase activity has been associated with severe malaria in studies of Indonesian adults [2], Malian children [9], and Tanzanian children [10]. The latter study also demonstrated elevated peripheral blood mononuclear cell arginase 1 messenger RNA expression [10]. However, unlike sickle cell disease, in which the decreased ratio of plasma levels of arginine to ornithine is consistent with elevated arginase activity [11], patients with severe malaria exhibit profound depletion of both arginine and ornithine [2,12], leaving the ratio of arginine to ornithine levels unchanged [2].…”

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

“…Luty et al found remarkably similar correlations with parasitemia and plasma IL-10, TNF, and IL-12p70 levels among Gabonese children with uncomplicated and severe malaria (40). Weinberg et al also demonstrated similarly elevated plasma levels of IL-10 in Tanzanian children with moderately severe and severe malaria, with IL-10 levels showing a significant correlation with disease severity as well as monocyte polarization toward an M2 phenotype with high levels of arginase 1 and low levels of NOS2 expression (which may contribute to NO insufficiency and oxidative stress) (41). Collectively, these observations suggest that oxidative stress related to heme and/or hemozoin toxicity to phagocytes may enhance IL-10 production while downregulating IL-12 activity (42).…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…89 Increased arginase activity has also been demonstrated in monocytes of the M2 phenotype in children with falciparum malaria. 90 However, in all the above studies concerning the role of NO in severe malaria, microvascular permeability was not directly measured. The readouts were reactive hyperemiaperipheral arterial tonometry, which is more a measure of vascular tone, and gaseous exchange that could be affected by perfusion.…”